Methods For Fabricating Coatings For Drug Delivery Devices Having Gradient Of Hydration

ABSTRACT

A method for fabricating a coating for an implantable medical device is provided comprising applying a first polymer on at least a portion of the device to form a first layer of the coating and applying a second polymer on at least a portion of the first layer to form a second layer of the coating. The second polymer has a lower degree of hydration than the first polymer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 10/703,334, filed on Nov. 6, 2003, the entire disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to coatings for implantable medical devices,such as drug eluting vascular stents.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer. Once the stent hasbeen implanted at the treatment site, the therapeutic substance has asustained release profile from the polymer.

Local administration of therapeutic agents via stents has shown somefavorable results in reducing restenosis. However, these results can befurther improved. For example, it is desirable to further improve theoverall biocompatibility and non-fouling properties of the stent. It isalso desirable to be able to better control the rate of the release ofthe drug from the coating. The embodiments of the present invention aredirected to coatings that satisfy these and other needs.

SUMMARY

According to one embodiment of this invention, a method for fabricatinga coating for an implantable medical device is provided, the methodcomprising applying a first polymer on at least a portion of the deviceto form a first layer of the coating, and applying a second polymer onat least a portion of the first layer to form a second layer of thecoating, wherein the second polymer has a lower degree of hydration thanthe first polymer. Optionally, the coating can additionally include athird layer, the third layer comprising a third polymer, the third layerbeing disposed over at least a portion of the second layer, wherein thethird polymer has a lower degree of hydration than the second polymer ora higher degree of hydration than the second polymer.

The first polymer can have a degree of hydration between greater than 0%and about 20% by mass. The second polymer can have a degree of hydrationbetween greater than 0% and about 20% by mass. The third polymer canhave a degree of hydration between greater than 0% and about 50% bymass.

Examples of the first polymer that can be used include polyorthoesters,poly(butyleneterephthalate-co-ethylene glycol), poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol),poly(butyl methacrylate) (PBMA), poly(n-butyl methacrylate), poly(ethylmethacrylate), poly(methyl methacrylate), poly(n-propyl methacrylate),polymethacrylates, poly(D,L-lactide), poly(caprolactone),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(hydroxyvalerate),poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), polybutyral,poly(ethylene-co-vinyl acetate), poly(vinyl acetate), poly(vinylidenefluoride), poly(vinylidene fluoride-co-hexafluoropropene),poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyurethanes, andblends thereof.

Examples of the second polymer that can be used include polyorthoesters,poly(butyleneterephthalate-co-ethylene glycol), poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol),polyorthoesters having poly(ethylene glycol) (PEG) incorporated into thepolymer backbone, copolymers of alkyl methacrylates and 2-hydroxyethylmethacrylate, copolymers of PEG-acrylates and alkyl methacrylates,copolymers of PEG-methacrylates and alkyl methacrylates,poly(ester-amides) with PEG functionality, derivatives of hyaluronicacid, heparin conjugates, sulfonated polystyrenes, andpoly(ethylene-co-vinyl alcohol) with pendant PEG functionality,poly(n-butyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), poly(n-propyl methacrylate), polymethacrylates,poly(D,L-lactide), poly(caprolactone), poly(4-hydroxybutyrate),poly(3-hydroxybutyrate), poly(hydroxyvalerate), poly(ethylene-co-vinylalcohol), poly(vinyl alcohol), poly(ethylene-co-vinyl acetate),poly(vinyl acetate), poly(vinylidene fluoride), poly(vinylidenefluoride-co-hexafluoropropene), poly(vinylidenefluoride-co-chlorotrifluoroethylene), polyurethanes, and blends thereof.

Examples of the third polymer that can be used include polyorthoesters,poly(butyleneterephthalate-co-ethylene glycol), poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol),polyorthoesters having poly(ethylene glycol) incorporated into thepolymer backbone, copolymers of alkyl methacrylates and 2-hydroxyethylmethacrylate, copolymers of poly(ethylene glycol)-acrylates and alkylmethacrylates, copolymers of poly(ethylene glycol)-methacrylates andalkyl methacrylates, poly(ester-amides) with poly(ethylene glycol)functionality, derivatives of hyaluronic acid, heparin conjugates,sulfonated polystyrenes, and poly(ethylene-co-vinyl alcohol) withpendant poly(ethylene glycol) functionality.

Alternatively, examples of the other first polymer, the second polymeror the third polymer that can be used include poly(hydroxyvalerate),poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lacticacid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate),co-poly(ether-esters), polyethylene oxide-co-polylactic acid,polyalkylene oxalates, polyphosphazenes, biomolecules, fibrin,fibrinogen, cellulose, starch, collagen, hyaluronic acid, polyurethanes,silicones, polyesters, polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers, polyvinyl chloride, polyvinyl ethers,polyvinyl methyl ether, polyvinylidene halides, polyvinylidene fluoride,poly(vinylidene fluoride-co-hexafluoropropene), poly(vinylidenefluoride-co-chlorotrifluoroethylene), polyvinylidene chloride,polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, polystyrene,polyvinyl esters, polyvinyl acetate, copolymers of vinyl monomers witheach other and olefins, ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetatecopolymers, polyamides, Nylon 66, polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, soluble fluorinatedpolymers and carboxymethyl cellulose.

The polyorthoesters that can be used as the first, the second, and thethird polymer are products of co-polycondensation of a diketene acetal,a hydroxylated functional compound and a diol. One example of a suitablepolyorthoester has the formula

wherein R and R₁, is each, independently, an unsubstituted orsubstituted straight-chained, branched, or cyclic C₁-C₈ alkyl radical,or unsusbstituted or substituted aryl radical; R₂—O is a non-foulingmoiety derived from a hydroxylated functional compound; R₃ is analiphatic or cycloaliphatic group; m, n, p, and q are all integers,where the value of m is between 5 and 500, the value of n is between 2and 350, the value of p is between 1 and 20, and the value of q isbetween 10 and 550.

DETAILED DESCRIPTION

A coating for an implantable medical device, such as a stent, accordingto embodiments of the present invention, can include any combination ofa primer layer, a drug-polymer layer (also referred to as “reservoir” or“reservoir layer”), and a topcoat layer. Possible combination of layersin the stent coating can include:

(a) the primer layer and the reservoir layer without the topcoat layer;

(b) the reservoir layer and the topcoat layer without the primer layer;and

(c) all three layers.

The drug-polymer layer serves as a reservoir for the drug. The reservoirlayer can be applied directly onto the stent surface. The primer layercan be applied on the stent surface to improve the adhesion of thedrug-polymer layer to the stent. The primer layer, if used, is theinnermost layer of the coating. The topcoat layer, which can beessentially free from any drugs, can serve as a rate limiting membraneto help control the release of the drug. The topcoat layer can alsoserve as a non-fouling, or hemocompatible layer, to enhance thebiocompatibility of the system. The topcoat layer, if used, can be theoutermost layer of the coating.

According to embodiments of the present invention, the layers of thestent are fabricated of polymers which can be hydrated to varyingdegrees. The terms “hydrated” and “hydration” refer to the ability of apolymer to absorb water at a temperature between the room temperature(e.g., about 20° C.) and the body temperature (about 37° C.) and ambientpressure. To determine the degree of hydration, a polymer can be eitherimmersed in water or exposed to 100% humid atmosphere for a period oftime needed to reach the absorption equilibrium (e.g., until the polymerhas absorbed maximum possible amount of water).

The degree of hydration for a particular polymer is determined by thepolymer's chemical and physical structure. The degree of hydration canbe calculated as a ratio between the mass of the water uptake achievedand the total mass of the polymer and water. To illustrate, if 9 gramsof a polymer have absorbed 1 gram of water under the above-describedconditions, the degree of hydration is 10% by mass. Generally, thepolymer included in each layer of the coating can have a degree ofhydration between greater than 0 and about 20 mass %, for example,between about 1 mass % and about 6 mass %, such as about 5 mass %. Thepolymer included in the topcoat layer, if the topcoat layer is used, canhave a degree of hydration between greater than 0 and about 50 mass %.Given the polymer and water densities, the degree of hydration by masscan be readily converted to the degree of hydration by volume. Thedimensional change in a polymer upon immersion in water can be also usedto determine percent hydration by volume.

The coating of the present invention can have a gradient of theconcentration of water in the coating. To achieve the gradient, for astent coating comprising the primer, the drug-polymer and the topcoatlayers, a polymer included in the primer can have the lowest degree ofhydration of the three layers, the polymer included in the topcoat layercan have the highest degree of hydration, and the polymer included inthe drug-polymer layer can have the intermediate degree of hydration.Alternatively, the polymer included in the primer can have the highestdegree of hydration of the three layers, the polymer included in thetopcoat layer can have the lowest degree of hydration, and the polymerincluded in the drug-polymer layer can have the intermediate degree ofhydration.

As another alternative, the polymers included in the primer and in thedrug-polymer layer can have the same degree of hydration, and thepolymer included in the topcoat layer can have a degree of hydrationthat is either higher or lower than that of the polymers included in theprimer and the drug-polymer layer. As yet another alternative, thepolymers included in the drug-polymer layer and the topcoat layer canhave the same degree of hydration, and the polymer included in theprimer can have a degree of hydration that is either higher or lowerthan that of the polymers included in the drug-polymer layer and thetopcoat layer.

For a stent coating comprising only the primer and the drug-polymerlayer, the polymer included in the primer can have the degree ofhydration that is lower than that of the polymer included in thedrug-polymer layer. In another embodiment, for a stent coatingcomprising only the primer and the drug-polymer layers, the polymerincluded in the primer can have the degree of hydration that is higherthan that of the polymer included in the drug-polymer layer.

For a stent coating comprising only the drug-polymer and the topcoatlayer, the polymer included in the drug-polymer layer can have thedegree of hydration that is lower than that of the polymer included inthe topcoat layer. In another embodiment, for a stent coating comprisingonly the drug-polymer and the topcoat layers, the polymer included inthe drug-polymer layer can have the degree of hydration that is higherthan that of the polymer included in the topcoat layer.

Examples of polymers that can be used to fabricate the primer layerinclude polyorthoesters, poly(butyleneterephthalate-co-ethylene glycol)(PBT-PEG), poly(ethylene glycol)-block-poly(butyleneterephthalate)-blockpoly(ethylene glycol) (PEG-PBT-PEG or POLYACTIVE), poly(n-butylmethacrylate) (PBMA), poly(D,L-lactide), poly(caprolactone),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(hydroxyvalerate),poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), polybutyral,poly(ethylene-co-vinyl acetate), poly(vinyl acetate), polyurethanes, andblends thereof.

POLYACTIVE is a trade name of a family of PEG-PBT-PEG polymers and isavailable from IsoTis Corp. of Holland. In various grades of POLYACTIVE,the ratio between the units derived from ethylene glycol and the unitsderived from butyleneterephthalate can be between about 0.67:1 and about9:1. The molecular weight of the units derived from ethylene glycol canbe between about 300 Daltons and about 4,000 Daltons. The overallweight-averaged molecular weight (M_(w)) of the POLYACTIVE polymers canbe between about 75,000 Daltons and about 125,000 Daltons. To make theprimer, a grade of POLYACTIVE can be used having a molecular weight ofthe ethylene glycol-derived units of about 300 and having a ratiobetween the ethylene glycol-derived units and the butyleneterephthalate-derived units of about 1.22:1 (about 55:45).

Examples of polymers that can be used for fabricating the drug-polymerlayer include polyorthoesters, PBT-PEG, POLYACTIVE, poly(n-butylmethacrylate), poly(ethyl methacrylate), poly(methyl methacrylate),poly(n-propyl methacrylate), other polymethacrylates, poly(D,L-lactide),poly(caprolactone), poly(4-hydroxybutyrate), poly(3-hydroxybutyrate),poly(hydroxyvalerate), poly(ethylene-co-vinyl alcohol), poly(vinylalcohol), poly(ethylene-co-vinyl acetate), poly(vinyl acetate),poly(vinylidene fluoride), poly(vinylidenefluoride-co-hexafluoropropene), poly(vinylidenefluoride-co-chlorotrifluoroethylene), polyurethanes, and blends thereof.The same or a different grade of POLYACTIVE can be used as the one usedfor making the primer.

Examples of polymers that can be used for fabricating the topcoat layerinclude polyorthoesters, PBT-PEG, POLYACTIVE, polyorthoesters withpoly(ethylene glycol)(PEG) incorporated into the polymer backbone,copolymers of alkyl methacrylates and 2-hydroxyethyl methacrylate,copolymers of PEG-acrylates and alkyl methacrylates, copolymers ofPEG-methacrylates and alkyl methacrylates, poly(ester-amides) with PEGfunctionality, derivatives of hyaluronic acid, heparin conjugates,sulfonated polystyrenes, and poly(ethylene-co-vinyl alcohol) withpendant PEG functionality. To make the topcoat layer, a grade ofPOLYACTIVE can be used having the molecular weight of the ethyleneglycol-derived units of about 4,000 and having the ratio between theethylene glycol-derived units and the butylene terephthalate-derivedunits of about 4:1 (about 80:20).

As indicated above, polyorthoesters are one class of polymers that canbe used to make any or all of the layers. The polyorthoesters that aresuitable for making stent coatings are products of co-polycondensationof at least one compound of Group I (a diketene acetal) with at leastone compound of Group II (a hydroxy functional compound) and with atleast one compound of Group III (a diol). Groups I, II, and III, andparticular compounds that are included in these Groups are describedbelow.

By selecting particular compounds of each of the Groups I, II and III,polyorthoesters having any desired degree of hydration can besynthesized. Following the synthesis, the polyorthoester can be used tomake a particular coating layer in accordance with the degree ofhydration of the polyorthoester. Thus, polyorthoesters having the degreeof hydration less than 10 vol. % can be used to make the primer, thepolyorthoesters having the degree of hydration between 0.5 and 10 vol. %can be used to make the drug-polymer layer, and the polyorthoestershaving the degree of hydration more than 10 vol. % can be used to makethe topcoat.

Group I. Diketene Acetals

Diketene acetals have a general formula (I)

where R and R₁ can be, independently, unsusbstituted or substitutedstraight-chained, branched, or cyclic C₁-C₈ alkyl radicals, orunsusbstituted or substituted aryl radicals. Any suitable substitutentto be selected by those having ordinary skill in the art can be presentin the substituted radicals.

Examples of diketene acetals described by formula (I) that can be usedinclude 3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane (DETOSU),3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane (DPTOSH),3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane,3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane and mixturesthereof. Those having ordinary skill in the art can synthesize diketeneacetals, as described in the literature, for example, in Heller J., Adv.Polymer Sci., vol. 107, pp. 41-92 (1993).

If both R and R₁ in formula (I) are methyl groups, formula (I) describesthe molecule of DETOSU. For DPTOSH, both R and R₁ in formula (I) aren-butyl groups.

Consequently, DETOSU has the formula (IIA) and DPTOSH has the formula(IIB):

Group II. Hydroxy Functional Compounds

Group II comprises hydroxylated compounds having at least one hydroxylgroup. The hydroxyl group can be located in a terminal or non-terminalposition of the molecule. Examples of hydroxy functional compounds thatcan be used include poly(alkylene glycols), for example, poly(ethyleneglycol) (PEG), poly(propylene glycol) (PPG) or poly(tetramethyleneglycol), PLURONIC surfactants, hydroxylated poly(vinyl pyrrolidone),dextran, dextrin, hyaluronic acid and derivatives thereof, such assodium hyaluronate, and poly(2-hydroxyethyl methacrylate), or mixturesthereof. PLURONIC is a trade name of poly(ethylene oxide-co-propyleneoxide) and is available from BASF Corp. of Parsippany, N.J.

A molecular weight of a suitable compound of Group II can be such so asto allow passage of the released molecule through the kidneys, forexample, below 40,000 Daltons, such as between about 300 and 20,000Daltons.

Compounds of Group II can be described by a general formula (ITT):

HO[—R₂—O—]_(m)H  (III)

where “m” is an integer, and —R₂—O— represents the moiety of compound(III) providing non-fouling characteristics. For example, when compound(III) is a poly(alkylene glycol), R₂ is the polymethylene structure(CH₂)_(x), where “x” is an integer. To illustrate, in case of compound(III) being PEG, x=2.

Group III. Diols

Group III comprises short-to-moderate-length (e.g., C₁ through C₁₆)aliphatic or cycloaliphatic diols or blends or combinations thereof.Examples of diols that can be used include alkylene glycols, forexample, C₂ through C₁₆ α,ω-glycols such as ethylene glycol (C₂₋),propane-1,2-diol (C₃₋), propane-1,3-diol (C₃₋), butane-1,4-diol (C₄),pentane-1,5-diol (C₅), hexane-1,6-diol (C₆), heptane-1,7-diol (C₇),octane-1,8-diol (C₈), nonane-1,9-diol (C₉), decane-1,10-diol (C₁₀),undecane-1,11-diol (C₁₁), dodecane-1,12-diol (C₁₂), tridecane-1,13-diol(C₁₃), tetradecane-1,14-diol (C₁₄), pentadecane-1,15-diol (C₁₅),hexadecane-1,16-diol (C₁₆), or mixtures thereof, or other alkyleneglycols, for example, butane-1,3-diol, pentane-2,4-diol,hexane-2,5-diol, or mixtures thereof. Other aliphatic diols that can beused include oligoalkylene glycols such as diethylene glycol,trimethylene glycol, tetramethylene glycol, tetraethylene glycol,poly(tetraethylene glycol), poly(propylene glycol), and mixturesthereof. Examples of cycloaliphatic diols that can be used includetrans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.

Compounds of Group III can be described by a general formula (IV):

HO—R₃—OH  (IV)

where R₃ represents an aliphatic or cycloaliphatic group. For example,when compound (IV) is an alkylene glycol, R₃ is the poly- oroligomethylene structure (CH₂)_(y), where “y” is an integer between 2and 16. To illustrate, when compound (IV) is ethylene glycol, y=2. Incase of propane-1,3-diol (C₃), y=3.

One way of preparing polyorthoesters is a to use a two-step syntheticprocess. The first step includes reacting the whole amount of diketeneacetal of Group I with a hydroxy functional compound of Group II. Thereaction (“reaction 1”) can be conducted in anhydrous environment at anelevated temperature, for example, about 80° C., and can be catalyzed bya strong acid or base, e.g., p-toluenesulfonic acid. The second stepincludes adding a diol of Group III to the product of reaction 1, whichcan be conducted at an elevated temperature, for example, about 80° C.As a result of the two-step process described above, a polyorthoestercan be obtained, the polyorthoester having a general formula (V):

where R, R₁, R₂, and R₃ are as described above; m, n, p, and q are allintegers, where the value of m is between about 5 and about 500, thevalue of n is between about 2 and about 350, the value of p is betweenabout 1 and about 20, and the value of q is between about 10 and about550. The polyorthoester described by formula (V) can have molecularweight within a range of between about 20,000 and about 200,000 Daltons.

In addition, other (alternative) polymers can be used to make the stentcoatings. The alternative polymers can be used instead of, or in acombination with, the above-described polymers. A variety of thealternative polymers can be used so long as the degree of hydration ofthe alternative polymer is within the limits specified above for theprimer, drug-polymer and/or the topcoat layer.

Representative examples of other polymers that can be used includepoly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane; poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers (such as polyvinyl chloride), polyvinylethers (such as polyvinyl methyl ether), polyvinylidene halides, such aspolyvinylidene fluoride, poly(vinylidene fluoride-co-hexafluoropropene),poly(vinylidene fluoride-co-chlorotrifluoroethylene) and polyvinylidenechloride; polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),copolymers of vinyl monomers with each other and olefins (such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers),polyamides (such as Nylon 66 and polycaprolactam), alkyd resins, otherpolycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,other polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, solublefluorinated polymers and carboxymethyl cellulose.

The drug can include any substance capable of exerting a therapeutic orprophylactic effect for a patient. The drug may include small moleculedrugs, peptides, proteins, oligonucleotides, and the like. The drugcould be designed, for example, to inhibit the activity of vascularsmooth muscle cells. It can be directed at inhibiting abnormal orinappropriate migration and/or proliferation of smooth muscle cells toinhibit restenosis.

Examples of drugs include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich, or COSMEGEN available from Merck). Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycin I₁,actinomycin X₁, and actinomycin C₁. The active agent can also fall underthe genus of antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

The stent, or other implantable medical device can be used in any partof the vascular system, including neurological, carotid, coronary,renal, aortic, iliac, femoral or any other part of the peripheralvasculature. The are no limitations on the size of the stent, itslength, diameter, strut thickness or pattern. Examples of suchimplantable devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts). The coating can alsobe used with artificial heart valves, cerebrospinal fluid shunts,coronary shunts, pacemaker electrodes, and endocardial leads (e.g.,FINELINE and ENDOTAK, available from Guidant Corporation). Theunderlying structure of the device can be of virtually any design. Thedevice can be made of a metallic material or an alloy such as, but notlimited to, cobalt chromium alloy (ELGILOY), cobalt chromium alloyL-605, stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromstandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

The following examples demonstrate some embodiments of the presentinvention.

EXAMPLE 1 Synthesis of poly(ethyleneglycol-co-3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane-co-1,4-butanediol)(PEG-DETOSU-BD)

About 25 g (12.5 mmol) of PEG having molecular weight (M_(w)) of about2,000 can be placed into a 1-liter round bottom flask equipped with amechanical stirrer. PEG can be treated to remove water by being heatedto about 80° C. using an oil bath, while being stirred under vacuum ofabout 25 mm Hg. About 400 g of tetrahydrofuran (THF) and about 5.74 g(27.08 mmol) of DETOSU can be added to the flask and dissolved withcontinued stirring. A solution of p-toluenesulfonic acid in THF havingconcentration of about 25 g/l can be prepared and about 10 drops of thissolution can be added to the contents of the flask. The stirring cancontinue for about 1 hour while the contents of the flask are maintainedat about 80° C. About 8.53 g (16.67 mmol) of 1,4-butanediol can then beadded to the flask, and the stirring can continue for about 1 more hourwhile the contents of the flask are continued to be kept at about 80° C.The reaction mixture then can be cooled and about 1 liter of hexane canbe added. As a result, the polyorthoester PEG-DETOSU-BD, can becollected by filtration. The polymer can then be purified by dissolutionin dry methanol or chloroform and precipitated with hexane.

The structure of PEG-DETOSU-BD can be described by formula (VI)

where R and R₁ is each CH₃, R₂ is (CH₂)₂, R₃ is (CH₂)₄, m=45, n=13, p=1,and q=17 (the values of m, n, p, and q are rounded to the nearestinteger). PEG-DETOSU-BD is quite hydrophilic and is expected to have thedegree of hydration of between about 25 vol. % and about 50 vol. %, forexample, about 40 vol. %.

EXAMPLE 2 Synthesis ofpoly(trans-cyclohexanedimethanol)-co-3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane-co-1,6-hexanediol(CHDM-DETO SU-HD)

A poly(ortho ester) can be synthesized of DETOSU and a diol component.The diol component can comprise a mixture of trans-cyclohexanedimethanol(CHDM) and 1,6-hexanediol (HD), the mixture having the molar ratiobetween CHDM and HD of about 7:3. A synthesis method described inExample 1 can be used. CHDM-DETOSU-HDjis quite hydrophobic and isexpected to have the degree of hydration of less than about 1 vol. %.

EXAMPLE 3 Synthesis ofpoly(3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane-co-1,10-decanediol(DETOSU-DD)

About 13.94 g (80 mmol) of 1,10-decanediol can be placed into a 500 mlround bottom flask equipped with a mechanical stirrer. Water can beremoved form the diol by heating it above melting to about 80° C. usingan oil bath, while being stirred under a vacuum of about 25 mm Hg. About100 ml of THF and about 16.98 g (80 mmol) of DETOSU can be added to theflask and dissolved with stirring. A solution of p-toluenesulphonic acidin THF having a concentration of about 1 mass % can be prepared andabout 12 drops of this solution can be added to the contents of theflask. The stirring can continue for about 1 hour while the contents ofthe flask are maintained at about 80° C. The reaction mixture can becooled and the polymer isolated on a rotoevaporator. The polymer canthen be purified by dissolution in dry methanol or chloroform, followedby precipitation with hexane. DETOSU-DD is quite hydrophobic and isexpected to have a degree of hydration of less than about 1 vol. %.

EXAMPLE 4

A first composition can be prepared by mixing the following components:

(a) about 2.0 mass % CHDM-DETOSU-HD synthesized as described in Example2; and

(b) the balance, a solvent blend of trichloroethane and tetrahydrofuranat a mass ratio of about 1:1.

The first composition can be applied onto the surface of a bare 18 mmVISION stent (available from Guidant Corp.) by spraying and dried toform a primer layer. An EFD spray head can be used, having a 0.014 inchround nozzle tip and a 0.028 inch round air cap with a feed pressure ofabout 0.2 atm (3 psi) and an atomization pressure of between about 1 atmand 1.3 atm (15 to 20 psi). The total amount of solids of the primerlayer can be about 120 micrograms (μg). After spraying, the stents canbe baked at about 55° C. for about one hour. “Solids” means the amountof dry residue deposited on the stent after all volatile organiccompounds (e.g. the solvent) have been removed.

A second composition can be prepared by mixing the following components:

(a) about 4 mass % DETOSU-DD synthesized as described in Example 3;

(b) about 1 mass % EVEROLIMUS; and

(c) the balance, a solvent blend of trichloroethane and tetrahydrofuranat a mass ratio of about 1:1.

The second composition can be applied onto the dried primer to form adrug-polymer layer, using the same spraying technique and equipment usedfor applying the primer layer. Solvent can be removed by baking at about50° C. for about one hour. The total amount of solids of thedrug-polymer layer can be about 832 μg.

A third composition can be prepared by mixing the following components:

(a) about 2 mass % PEG-DETOSU-BD obtained as described in Example 1;

(b) the balance, a solvent blend of acetone and cyclohexanone at a massratio of about 1:1.

The third composition can be applied onto the dried reservoir layer,using the same spraying technique and equipment used for applying theprimer and drug-polymer layers to form a topcoat layer. Solvent can beremoved by baking at 50° C. for one hour. The total amount of solids ofthe topcoat layer can be about 100 μg.

EXAMPLE 5

A first composition can be prepared by mixing the following components:

(a) about 2.0 mass % PEG-PBT-PEG (POLYACTIVE); and

(b) the balance, a solvent blend, the blend comprising1,1,2-tricloroethane and chloroform in a mass ratio between1,1,2-tricloroethane and chloroform of about 4:1.

The grade of POLYACTIVE that can be used can have about 45 molar % unitsderived from PBT and about 55 molar % units derived from PEG. Themolecular weight of the PEG units can be about 300 Daltons. The overallweight-averaged molecular weight (M_(w)) of POLYACTIVE can be betweenabout 75,000 Daltons and about 125,000 Daltons. The first compositioncan be applied onto the surface of a bare 12 mm VISION stent (availablefrom Guidant Corporation) by spraying, using the spraying technique andequipment described in Example 4 and dried to form a primer layer. Theprimer can be baked at about 140° C. for about 1 hour to yield a dryprimer layer having solids content of about 100 μg.

A second composition can be prepared by mixing the following components:

(a) about 2 mass % POLYACTIVE;

(b) about 1 mass % paclitaxel; and

(c) the balance, the blend of 1,1,2-tricloroethane and chloroformdescribed above.

The same grade of POLYACTIVE as that utilized for making the primerlayer can be used. The second composition can be applied onto the driedprimer layer, using the same spraying technique and equipment used forapplying the primer layer, to form the drug-polymer layer. The secondcomposition can be baked at about 50° C. for about 1 hour, yielding adry drug-polymer layer having solids content of about 400 μg.

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % POLYACTIVE having about 45 molar % units derivedfrom PBT and about 55 molar % units derived from PEG, as describedabove;

(b) about 2.0 mass % POLYACTIVE having about 20 molar % units derivedfrom PBT and about 80 molar % units derived from PEG, where themolecular weight of the PEG units can be about 4,000 Daltons and theoverall M_(w) of this grade of POLYACTIVE can be between about 75,000Daltons and about 125,000 Daltons; and

(c) the balance, the blend of 1,1,2-tricloroethane and chloroformdescribed above.

The third composition can be applied onto the dried drug-polymer layers,using the same spraying technique and equipment used for applying theprimer land drug-polymer layers, to form a topcoat layer. The thirdcomposition can be baked at about 50° C. for about 2 hours, yielding adry topcoat layer having solids content of about 100 μg.

EXAMPLE 6

A first composition can be prepared by mixing the following components:

(a) about 2.0 mass % poly(n-butyl methacrylate) (PBMA); and

(b) the balance, a solvent bland comprising acetone and cyclohexanone ina mass ratio of about 1:1.

The PBMA solution can be applied onto the surface of a bare 18 mm VISIONstent by spraying, using the spraying technique and equipment describedin Example 4, and dried to form a primer layer. The primer layer can bebaked at about 80° C. for about 30 minutes to yield a dry primer layerhaving solids content of about 120 μg.

A second composition can be prepared by mixing the following components:

(a) about 3 mass % poly(n-butylmethacrylate-co-(2-hydroxyethyl)methacrylate) having about 80 mass % ofthe units derived from n-butyl methacrylate, and the balance, the unitsderived from (2-hydroxyethyl)methacrylate;

(b) about 1 mass % EVEROLIMUS; and

(c) the balance, a solvent blend comprising dimethylacetamide andacetone in a mass ratio of about 7:3.

The second composition can be applied onto the dried primer layer, usingthe same spraying technique and equipment used for applying the primerlayer, to form the drug-polymer layer. The second composition can bebaked at about 50° C. for about 1 hour, yielding a dry drug-polymerlayer having solids content of about 640 μg.

Next, a methoxy terminated poly(ethylene glycol)-block-co-poly(n-butylmethacrylate) (mPEG-PBMA) can be synthesized. mPEG-PBMA is an AB blockcopolymer. The term “AB block copolymer” is defined as a block-copolymercontain polymeric moieties A and B. The AB block-copolymers can bedescribed by the formula [-A-A-A]_(m)-[B-B-B-]_(n), where each of “m”and “n,” is an integer greater than 0. The blocks of the AB blockcopolymers need not be linked on the ends, since the values of “m” and“n” are such as to ensure that the individual blocks are usually longenough to be considered polymers in their own right. In mPEG-PBMA, A isa poly(ethylene glycol) moiety, and B is a PBMA moiety. mPEG isavailable from Nektar Corp. (formerly, Shearwater Corp.) of Huntsville,Ala.

Those having ordinary skill in the art, can use a variety of synthetictechniques to prepare mPEG-PBMA. One synthetic method that can be usedincludes a two-step process. First, mPEG having molecular weight ofabout 5,000 can be functionalized with 2-bromoisobutyryl bromide. Thepath of functionalization is expected to include a reaction of terminalhydroxyl of mPEG with bromoisobutyryl bromide, yielding a brominatedderivative of mPEG, as shown by the reaction scheme (VII):

The process of functionalization is followed by copolymerization ofn-butyl with methacrylate the ester that is a product of the reaction(VII). The step of copolymerization can be carried as livingcopolymerization catalyzed by copper bromide-amine ligand complex, asknown to those having ordinary skill in the art. The synthesis yieldsmPEG-PBMA AB block copolymer, the structure of which can be illustratedby the formula (VIII):

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % mPEG-PBMA of formula (VII) synthesized, asdescribed above, having the M_(w) between about 100,000 Daltons andabout 250,000 Daltons; and

(c) the balance, a solvent blend comprising 1,1,2, trichloroethane andchloroform in a mass ratio of about 1:1.

The third composition can be applied onto the dried drug-polymer layers,using the same spraying technique and equipment used for applying theprimer and drug-polymer layers, to form a topcoat layer. The thirdcomposition can be baked at about 80° C. for about 30 minutes, yieldinga dry topcoat layer having solids content of about 120 μg.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method for fabricating a coating for an implantable medical device,the method comprising applying a first polymer on at least a portion ofthe device to form a first layer of the coating, and applying a secondpolymer on at least a portion of the first layer to form a second layerof the coating, wherein the second polymer has a lower degree ofhydration than the first polymer.
 2. The method of claim 1, wherein theimplantable medical device is a stent.
 3. The method of claim 1, whereinthe degree of hydration of the first polymer is between greater than 0%and about 20% by mass.
 4. The method of claim 1, wherein the degree ofhydration of the second polymer is between greater than 0% and about 20%by mass.
 5. The method of claim 1, wherein the first polymer is selectedfrom a group consisting of polyorthoesters,poly(butyleneterephthalate-co-ethylene glycol), poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol),poly(butyl methacrylate) (PBMA), poly(n-butyl methacrylate), poly(ethylmethacrylate), poly(methyl methacrylate), poly(n-propyl methacrylate),polymethacrylates, poly(D,L-lactide), poly(caprolactone),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(hydroxyvalerate),poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), polybutyral,poly(ethylene-co-vinyl acetate), poly(vinyl acetate), poly(vinylidenefluoride), poly(vinylidene fluoride-co-hexafluoropropene),poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyurethanes, andblends thereof.
 6. The method of claim 5, wherein the polyorthoestersare products of co-polycondensation of a diketene acetal, a hydroxylatedfunctional compound and a diol.
 7. The method of claim 6, wherein thediketene acetal has a formula

wherein R and R₁ are, independently, unsusbstituted or substitutedstraight-chained, branched, or cyclic C₁-C₈ alkyl radicals, andunsusbstituted or substituted aryl radicals.
 8. The method of claim 6,wherein the diketene acetal is selected from a group consisting of3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane,3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane,3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane,3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixturesthereof.
 9. The method of claim 6, wherein the hydroxylated functionalcompound comprises poly(alkylene glycols), PLURONIC surfactants(poly(ethylene oxide-co-propylene oxide)), hydroxylated poly(vinylpyrrolidone), dextran, dextrin, hyaluronic acid, derivatives ofhyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.10. The method of claim 9, wherein poly(alkylene glycols) are selectedfrom a group consisting of poly(ethylene glycol), poly(propyleneglycol), poly(propane-1,2-diol), poly(propane-1,3-diol) andpoly(tetramethylene glycol).
 11. The method of claim 6, wherein the diolcomprises alkylene glycols, oligoalkylene glycols, or cycloaliphaticdiols.
 12. The method of claim 11, wherein alkylene glycols are selectedfrom a group consisting of C₂ to C₁₆ α, ω-glycols.
 13. The method ofclaim 11, wherein alkylene glycols are selected from a group consistingof ethylene glycol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol,pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol, octane-1,8-diol,nonane-1,9-diol, decane-1,10-diol, undecane-1,11-diol,dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol,pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol,pentane-2,4-diol, hexane-2,5-diol, and mixtures thereof.
 14. The methodof claim 11, wherein oligoalkylene glycols are selected from a groupconsisting of diethylene glycol, trimethylene glycol, tetramethyleneglycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propyleneglycol), and mixtures thereof.
 15. The method of claim 11, whereincycloaliphatic diols are selected from a group consisting oftrans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.16. The method of claim 1, wherein the second polymer is selected from agroup consisting of polyorthoesters,poly(butyleneterephthalate-co-ethylene glycol), poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol),polyorthoesters having poly(ethylene glycol) (PEG) incorporated into thepolymer backbone, copolymers of alkyl methacrylates and 2-hydroxyethylmethacrylate, copolymers of PEG-acrylates and alkyl methacrylates,copolymers of PEG-methacrylates and alkyl methacrylates,poly(ester-amides) with PEG functionality, derivatives of hyaluronicacid, heparin conjugates, sulfonated polystyrenes, andpoly(ethylene-co-vinyl alcohol) with pendant PEG functionality,poly(n-butyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), poly(n-propyl methacrylate), polymethacrylates,poly(D,L-lactide), poly(caprolactone), poly(4-hydroxybutyrate),poly(3-hydroxybutyrate), poly(hydroxyvalerate), poly(ethylene-co-vinylalcohol), poly(vinyl alcohol), poly(ethylene-co-vinyl acetate),poly(vinyl acetate), poly(vinylidene fluoride), poly(vinylidenefluoride-co-hexafluoropropene), poly(vinylidenefluoride-co-chlorotrifluoroethylene), polyurethanes, and blends thereof.17. The method of claim 16, wherein the polyorthoesters are products ofco-polycondensation of a diketene acetal, a hydroxylated functionalcompound and a diol.
 18. The method of claim 17, wherein the diketeneacetal has a formula

wherein R and R₁ are, independently, unsusbstituted or substitutedstraight-chained, branched, or cyclic C₁-C₈ alkyl radicals, andunsusbstituted or substituted aryl radicals.
 19. The method of claim 17,wherein the diketene acetal is selected from a group consisting of3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane,3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane,3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane,3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixturesthereof.
 20. The method of claim 17, wherein the hydroxylated functionalcompound comprises poly(alkylene glycols), PLURONIC surfactants(poly(ethylene oxide-co-propylene oxide)), hydroxylated poly(vinylpyrrolidone), dextran, dextrin, hyaluronic acid, derivatives ofhyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.21. The method of claim 20, wherein poly(alkylene glycols) are selectedfrom a group consisting of poly(ethylene glycol), poly(propyleneglycol), poly(propane-1,2-diol), poly(propane-1,3-diol) andpoly(tetramethylene glycol).
 22. The method of claim 17, wherein thediol comprises alkylene glycols, oligoalkylene glycols, orcycloaliphatic diols.
 23. The method of claim 22, wherein alkyleneglycols are selected from a group consisting of C₂ to C₁₆ α, ω-glycols.24. The method of claim 22, wherein alkylene glycols are selected from agroup consisting of ethylene glycol, propane-1,2-diol, propane-1,3-diol,butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol,octane-1,8-diol, nonane-1,9-diol, decane-1,10-diol, undecane-1,11-diol,dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol,pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol,pentane-2,4-diol, hexane-2,5-diol, and mixtures thereof.
 25. The methodof claim 22, wherein oligoalkylene glycols are selected from a groupconsisting of diethylene glycol, trimethylene glycol, tetramethyleneglycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propyleneglycol), and mixtures thereof.
 26. The method of claim 22, whereincycloaliphatic diols are selected from a group consisting oftrans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.27. The method of claim 1, wherein the first polymer is a polymer havinga formula

wherein R and R₁, is each, independently, an unsusbstituted orsubstituted straight-chained, branched, or cyclic C₁-C₈ alkyl radical,or unsusbstituted or substituted aryl radical; R₂—O is a non-foulingmoiety derived from a hydroxylated functional compound; R₃ is analiphatic or cycloaliphatic group; m, n, p, and q are all integers,where the value of m is between 5 and 500, the value of n is between 2and 350, the value of p is between 1 and 20, and the value of q isbetween 10 and
 550. 28. The method of claim 27, wherein R₂ is apolymethylene structure.
 29. The method of claim 27, wherein thehydroxylated functional compound comprises poly(alkylene glycols),hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid,derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), ormixtures thereof.
 30. The method of claim 1, wherein the second polymeris a polymer having a formula

wherein R and R₁, is each, independently, an unsusbstituted orsubstituted straight-chained, branched, or cyclic C₁-C₈ alkyl radical,or unsusbstituted or substituted aryl radical; R₂—O is a non-foulingmoiety derived from a hydroxylated functional compound; R₃ is analiphatic or cycloaliphatic group; m, n, p, and q are all integers,where the value of m is between 5 and 500, the value of n is between 2and 350, the value of p is between 1 and 20, and the value of q isbetween 10 and
 550. 31. The method of claim 30, wherein R₂ is apolymethylene structure.
 32. The method of claim 30, wherein thehydroxylated functional compound comprises poly(alkylene glycols),hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid,derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), ormixtures thereof.
 33. The method of claim 1, additionally includingapplying a third polymer on at least a portion of the second layer,wherein the third polymer has a lower degree of hydration than thesecond polymer or a higher degree of hydration than the second polymer.34. The method of claim 33, wherein the degree of hydration of the thirdpolymer is between greater than 0 and about 50% by mass.
 35. The methodof claim 33, wherein the third polymer is selected from a groupconsisting of polyorthoesters, poly(butyleneterephthalate-co-ethyleneglycol), poly(ethylene glycol)-block-poly(butyleneterephthalate)-blockpoly(ethylene glycol), polyorthoesters having poly(ethylene glycol)incorporated into the polymer backbone, copolymers of alkylmethacrylates and 2-hydroxyethyl methacrylate, copolymers ofpoly(ethylene glycol)-acrylates and alkyl methacrylates, copolymers ofpoly(ethylene glycol)-methacrylates and alkyl methacrylates,poly(ester-amides) with poly(ethylene glycol) functionality, derivativesof hyaluronic acid, heparin conjugates, sulfonated polystyrenes, andpoly(ethylene-co-vinyl alcohol) with pendant poly(ethylene glycol)functionality.
 36. The method of claim 35, wherein the polyorthoestersare products of co-polycondensation of a diketene acetal, a hydroxylatedfunctional compound and a diol.
 37. The method of claim 36, wherein thediketene acetal has a formula

wherein R and R₁ are, independently, unsusbstituted or substitutedstraight-chained, branched, or cyclic C₁-C₈ alkyl radicals, andunsusbstituted or substituted aryl radicals.
 38. The method of claim 36,wherein the diketene acetal is selected from a group consisting of3,9-diethylidene-2,4,8,10-tetraoxaspiro-[5,5]-undecane,3,9-dipentylidene-2,4,8,10-tetraoxaspiro-[5,5]-heptadecane,3,9-dibutylidene-2,4,8,10-tetraoxaspiro-[5,5]-pentadecane,3,9-dipropylidene-2,4,8,10-tetraoxaspiro-[5,5]-tridecane, and mixturesthereof.
 39. The method of claim 36, wherein the hydroxylated functionalcompound comprises poly(alkylene glycols), PLURONIC surfactants(poly(ethylene oxide-co-propylene oxide)), hydroxylated poly(vinylpyrrolidone), dextran, dextrin, hyaluronic acid, derivatives ofhyaluronic acid, poly(2-hydroxyethyl methacrylate), or mixtures thereof.40. The method of claim 39, wherein poly(alkylene glycols) are selectedfrom a group consisting of poly(ethylene glycol), poly(propyleneglycol), poly(propane-1,2-diol), poly(propane-1,3-diol) andpoly(tetramethylene glycol).
 41. The method of claim 36, wherein thediol comprises alkylene glycols, oligoalkylene glycols, orcycloaliphatic diols.
 42. The method of claim 41, wherein alkyleneglycols are selected from a group consisting of C₂ to C₁₆ α, ω-glycols.43. The method of claim 41, wherein alkylene glycols are selected from agroup consisting of ethylene glycol, propane-1,2-diol, propane-1,3-diol,butane-1,4-diol, pentane-1,5-diol, hexane-1,6-diol, heptane-1,7-diol,octane-1,8-diol, nonane-1,9-diol, decane-1,10-diol, undecane-1,1′-diol,dodecane-1,12-diol, tridecane-1,13-diol, tetradecane-1,14-diol,pentadecane-1,15-diol, hexadecane-1,16-diol, butane-1,3-diol,pentane-2,4-diol, hexane-2,5-diol, and mixtures thereof.
 44. The methodof claim 41, wherein oligoalkylene glycols are selected from a groupconsisting of diethylene glycol, trimethylene glycol, tetramethyleneglycol, tetraethylene glycol, poly(tetraethylene glycol), poly(propyleneglycol), and mixtures thereof.
 45. The method of claim 41, whereincycloaliphatic diols are selected from a group consisting oftrans-cyclohexanedimethanol, 1,4-cyclohexanediol, and mixtures thereof.46. The method of claim 33, wherein the third polymer is a polymerhaving a formula

wherein R and R₁, is each, independently, an unsusbstituted orsubstituted straight-chained, branched, or cyclic C₁-C₈ alkyl radical,or unsusbstituted or substituted aryl radical; R₂—O is a non-foulingmoiety derived from a hydroxylated functional compound; R₃ is analiphatic or cycloaliphatic group; m, n, p, and q are all integers,where the value of m is between 5 and 500, the value of n is between 2and 350, the value of p is between 1 and 20, and the value of q isbetween 10 and
 550. 47. The method of claim 46, wherein R₂ is apolymethylene structure.
 48. The method of claim 46, wherein thehydroxylated functional compound comprises poly(alkylene glycols),hydroxylated poly(vinyl pyrrolidone), dextran, dextrin, hyaluronic acid,derivatives of hyaluronic acid, poly(2-hydroxymethyl methacrylate), ormixtures thereof.
 49. The method of claim 33, wherein the first polymer,the second polymer or the third polymer is selected from a groupconsisting of poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters), polyethyleneoxide-co-polylactic acid, polyalkylene oxalates, polyphosphazenes,biomolecules, fibrin, fibrinogen, cellulose, starch, collagen,hyaluronic acid, polyurethanes, silicones, polyesters, polyolefins,polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers andcopolymers, vinyl halide polymers and copolymers, polyvinyl chloride,polyvinyl ethers, polyvinyl methyl ether, polyvinylidene halides,polyvinylidene fluoride, poly(vinylidene fluoride-co-hexafluoropropene),poly(vinylidene fluoride-co-chlorotrifluoroethylene), polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics,polystyrene, polyvinyl esters, polyvinyl acetate, copolymers of vinylmonomers with each other and olefins, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinylacetate copolymers, polyamides, Nylon 66, polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, soluble fluorinatedpolymers and carboxymethyl cellulose.